FOXC2 Expression Links Epithelial–Mesenchymal Transition and Stem Cell Properties in Breast Cancer

Abstract

Resistance to chemotherapy and metastases are the major causes of breast cancer-related mortality. Moreover, cancer stem cells (CSCs) play critical roles in cancer progression and treatment resistance. Previously, it was found that CSC-like cells can be generated by aberrant activation of EMT, thereby making anti-EMT strategies a novel therapeutic option for treatment of aggressive breast cancers. Here, we report that the transcription factor FOXC2 induced in response to multiple EMT signaling pathways as well as elevated in stem cell-enriched factions is a critical determinant of mesenchymal and stem cell properties, in cells induced to undergo EMT and CSC-enriched breast cancer cell lines. More specifically, attenuation of FOXC2 expression using lentiviral short hairpin RNA led to inhibition of the mesenchymal phenotype and associated invasive and stem cell properties, which included reduced mammosphere forming ability and tumor initiation. Whereas, overexpression of FOXC2 was sufficient to induce CSC properties and spontaneous metastasis in transformed human mammary epithelial cells. Furthermore, a FOXC2-induced gene expression signature was enriched in the claudin-low/basal B breast tumor subtype that contains EMT and CSC features. Having identified PDGFR-β to be regulated by FOXC2, we demonstrate that the FDA-approved PDGFR inhibitor, sunitinib, targets FOXC2-expressing tumor cells leading to reduced CSC and metastatic properties. Thus, FOXC2 or its associated gene expression program may provide an effective target for anti-EMT based therapies for the treatment of claudin-low/basal B breast tumors or other EMT/CSC-enriched tumors.

Antagonists of IGF:Vitronectin Interactions Inhibit IGF-I–Induced Breast Cancer Cell Functions

“…Briefly, these HMLER-FOXC2 cells were prepared as described previously (19) and one million cells were injected subcutaneously in the flank of nude mice. Once tumors were 1,000 mm 3 , mice were euthanized and tumors collected as described previously (19). Tissue slices were cut to 5-mm thickness and stored.…”

“…Human TMAs derived from 14 breast cancer and 4 normal patient tissues (details in Supplementary Fig. S1), as well as tumor tissues collected from HMLER-FOXC2 xenografts (19), were analyzed with in situ PLA. In the xenograft tissues, the PLA signal for VN:IGFBP-3 was observed in the peri-cellular stroma (Fig.…”

FOXC2 Expression is Associated with Tumor Proliferation and Invasion Potential in Oral Tongue Squamous Cell Carcinoma

“…Regarding FOXC2 expression and invasion potential, FOXC2 expression was has been associated with EMT [19][20][21][22][23].…”

“…FOXC2 was previously associated with EMT [19][20][21][22][23] and tumor angiogenesis [24,25] in various cancers. Although a relationship has already been reported between the expression of FOXC2 and poor prognosis in various cancers [21,[26][27][28][29], those between the expression of FOXC2 and clinicopathological features in OSCC have not yet been investigated.…”

High Expression of Forkhead Box Protein C2 is Related to Poor Prognosis in Human Gliomas

“…Expression of FOXC2 protein was detected in a variety of cancers, including breast adenocarcinomas (Mani et al, 2007), ovarian cancer (Liu et al, 2014), colorectal cancer (Watanabe et al, 2011), cervical cancer (Zheng et al, 2014), gastric cancer (Zhu et al, 2013) and non-small-cell lung cancer (Jiang et al, 2012). Overexpression of FOXC2 has been reported in subtypes of breast cancer which are highly metastatic, suppression of FOXC2 expression using shRNA in a highly metastatic breast cancer model blocks their metastatic ability (Hollier et al, 2013). FOXC2 expression has also been reported in esophageal squamous cell cancer and could be used as a novel independent prognosis factor (Nishida et al, 2011).…”